Corticotropin releasing factor receptor antagonists

ABSTRACT

The present invention provides novel pharmaceutical compositions comprising -(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine and methods of using the same for the treatment of Congenital adrenal hyperplasia (CAH).

CROSS-REFERENCE

This patent application is a continuation of U.S. patent applicationSer. No. 17/586,228, filed Jan. 27, 2022; which is a divisional of U.S.patent application Ser. No. 17/359,411, filed on Jun. 25, 2021, now U.S.Pat. No. 11,351,177; which is a continuation of U.S. patent applicationSer. No. 17/063,592, filed on Oct. 5, 2020, now U.S. Pat. No.11,344,557; which is a continuation of U.S. patent application Ser. No.16/388,620, filed on Apr. 18, 2019, now U.S. Pat. No. 10,849,908; whichis a continuation of PCT Application No. PCT/US2018/046760, filed onAug. 14, 2018; which claims the benefit of U.S. Provisional PatentApplication No. 62/545,406, filed Aug. 14, 2017; each of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (CRF) is a 41 amino acid peptide that isthe primary physiological regulator of proopiomelanocortin (POMC)derived peptide secretion from the anterior pituitary gland. In additionto its endocrine role at the pituitary gland, immunohistochemicallocalization of CRF has demonstrated that the hormone has a broadextrahypothalamic distribution in the central nervous system andproduces a wide spectrum of autonomic, electrophysiological andbehavioral effects consistent with a neurotransmitter or neuromodulatorrole in the brain. There is also evidence that CRF plays a significantrole in integrating the response in the immune system to physiological,psychological, and immunological stressors.

SUMMARY OF THE INVENTION

The present invention provides novel pharmaceutical compositionscomprising3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidineand methods using such pharmaceutical compositions for treatingcongenital adrenal hyperplasia (CAH).

In one aspect, the present disclosure provides a method of treatingcongenital adrenal hyperplasia (CAH) in a subject in need thereof,comprising administering a pharmaceutical composition comprisingCompound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered at a dose between about 50 mg/dayand about 1200 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between about 50 mg/day and about 1000 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 50 mg/day andabout 800 mg/day. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered at a dose betweenabout 100 mg/day and about 600 mg/day. In some embodiments, Compound 1,or a pharmaceutically acceptable salt or solvate thereof, isadministered at a dose between about 200 mg/day and 400 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose of about 200 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is in the form of microparticles. In someembodiments, the average size of the microparticles is between about 1μm and about 20 μm. In some embodiments, the average size of themicroparticles is between about 5 μm and about 15 μm. In someembodiments, the average size of the microparticles is less than about10 μm.

In some embodiments, the pharmaceutical composition is in the form of acapsule or a tablet. In some embodiments, the pharmaceutical compositionis in the form of a capsule. In some embodiments, the capsule is a hardgelatin capsule. In some embodiments, the capsule is a soft gelatincapsule. In some embodiments, the capsule is formed using materialsselected from the group consisting of natural gelatin, syntheticgelatin, pectin, casein, collagen, protein, modified starch,polyvinylpyrrolidone, acrylic polymers, cellulose derivatives, and anycombinations thereof.

In some embodiments, the pharmaceutical composition is free ofadditional excipients. In some embodiments, the pharmaceuticalcomposition further comprises one or more pharmaceutically acceptableexcipients.

In some embodiments, the pharmaceutical composition is in the form of atablet. In some embodiments, the pharmaceutical composition furthercomprises one or more pharmaceutically acceptable excipients. In someembodiments, the pharmaceutical composition comprises between about 1 mgand about 500 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 5 mg and about 500 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 10mg and about 500 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 10 mg and about 300 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 10mg and about 100 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 50 mg and about 500 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 100mg and about 400 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 100 mg and about 300 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 150mg and about 250 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof.

In some embodiments, the pharmaceutical composition comprises about 400mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 300 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises about 250 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the pharmaceuticalcomposition comprises about 200 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises about 150 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition comprises about 80 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition comprises about 60mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 50 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof In some embodiments, the pharmaceutical compositioncomprises about 30 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the pharmaceutical composition provides a Compound1 T_(max) of about 2 to about 6 hours in a subject. In some embodiments,the pharmaceutical composition provides a Compound 1 T_(max) of about 3to about 5 hours in a subject. In some embodiments, the pharmaceuticalcomposition provides a Compound 1 T_(max) of about 6 hours in a subject.In some embodiments, the pharmaceutical composition provides a Compound1 T_(max) of about 5 hours in a subject. In some embodiments, thepharmaceutical composition provides a Compound 1 T_(max) of about 4hours in a subject. In some embodiments, the pharmaceutical compositionprovides a Compound 1 T_(max) of about 3 hours in a subject.

In some embodiments, the pharmaceutical composition is administered inthe fed state. In some embodiments, the pharmaceutical composition isadministered in the fasted state. In some embodiments, thepharmaceutical composition is administered once a day. In someembodiments, the pharmaceutical composition is administered twice a day.In some embodiments, the pharmaceutical composition is administeredthree times a day.

In some embodiments, the method further comprises administering aglucocorticoid. In some embodiments, the amount of glucocorticoidadministered is reduced as compared to a method not comprisingadministering Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the amount of glucocorticoid usedis reduced from a supraphysiologic amount to a physiologic amount. Insome embodiments, the amount of glucocorticoid is reduced by about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, or about 60%.

In some embodiments, the symptoms associated with high-doseglucocorticoid therapy are reduced. In some embodiments, the symptomsassociated with high-dose glucocorticoid therapy are obesity, insulinresistance, metabolic abnormalities, hypertension, cardiovasculardiseases, or osteoporosis. In some embodiments, the glucocorticoid isbeclomethasone, betamethasone, budesonide, cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone, ortriamcinolone.

In some embodiments, the glucocorticoid is hydrocortisone. In someembodiments, the hydrocortisone is administered at a dose less thanabout 15 mg/day. In some embodiments, the hydrocortisone is administeredat a dose less than about 10 mg/day. In some embodiments, thehydrocortisone is administered at a dose less than about 5 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, and the glucocorticoid are administeredconcurrently. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered sequentially. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered sequentially within 24 hours. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, and the glucocorticoid are administered sequentiallywithin 8 hours. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered sequentially within 2 hours. In some embodiments, Compound1, or a pharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered sequentially within 30 minutes.

In some embodiments, the method further comprises administering amineralocorticoid. In some embodiments, the mineralocorticoid isfludrocortisone.

In some embodiments, the pharmaceutical composition is administered atbedtime. In some embodiments, the pharmaceutical composition isadministered less than about 4 hours before sleep. In some embodiments,the pharmaceutical composition is administered less than about 2 hoursbefore sleep. In some embodiments, the pharmaceutical composition isadministered less than about 30 mins before sleep. In some embodiments,the pharmaceutical composition is administered in the evening. In someembodiments, the pharmaceutical composition is administered at about 10pm at night. In some embodiments, the pharmaceutical composition isadministered at or before the expected circadian release ofadrenocorticotropic hormone (ACTH). In some embodiments, thepharmaceutical composition is administered about 3-4 hours before theexpected circadian release of adrenocorticotropic hormone (ACTH).

In some embodiments, CAH is classic CAH. In some embodiments, CAH isnon-classic CAH.

In one aspect, the present disclosure provides a method of treatingcongenital adrenal hyperplasia (CAH) in a subject in need thereof, themethod comprising: (i) measuring a hormone level in the subject in needthereof; (ii) administering Compound 1:

or a pharmaceutically acceptable salt or solvate thereof; and(iii) repeating steps (i) and (ii) until the hormone level reaches apre-determined range followed by a maintenance therapy of a daily dosingof compound 1.

In some embodiments, the hormone is 17α-Hydroxyprogesterone (17-OHP),adrenocorticotropic hormone (ACTH), testosterone, or androstenedione. Insome embodiments, the hormone is 17-OHP, and the pre-determined range isfrom about 200 ng/dL to about 400 ng/dL. In some embodiments, thehormone is ACTH, and the pre-determined range is below about 100 pg/mL.In some embodiments, the hormone is testosterone and the pre-determinedrange is from about 14 ng/dL to about 76 ng/dL. In some embodiments, thehormone is androstenedione and the pre-determined range is from about 30ng/dL to about 150 ng/dL in males. In some embodiments, the hormone isandrostenedione and the pre-determined range is from about 40 ng/dL toabout 200 ng/dL in females.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered at a dose between about 200 mg/dayand about 1600 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between about 200 mg/day and about 1200 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 200 mg/day andabout 1000 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between about 200 mg/day and about 800 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 200 mg/day andabout 600 mg/day. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered at a dose betweenabout 200 mg/day and 400 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose of about 200 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered at a dose between about 50 mg/dayand about 1600 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between about 50 mg/day and about 1200 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 50 mg/day andabout 1000 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between about 50 mg/day and about 800 mg/day. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 50 mg/day andabout 600 mg/day. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered at a dose betweenabout 50 mg/day and 400 mg/day. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose between 50 mg/day and 200 mg/day. In some embodiments, Compound1, or a pharmaceutically acceptable salt or solvate thereof, isadministered at a dose of about 50 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is in the form of microparticles. In someembodiments, the average size of the microparticles is between about 1μm and about 20 μm. In some embodiments, the average size of themicroparticles is between about 5 μm and about 15 μm. In someembodiments, the average size of the microparticles is less than about10 μm.

In some embodiments, Compound 1 is formulated in a pharmaceuticalcomposition in the form of a capsule or a tablet. In some embodiments,the pharmaceutical composition is in the form of a capsule. In someembodiments, the capsule is a hard gelatin capsule. In some embodiments,the capsule is a soft gelatin capsule. In some embodiments, the capsuleis formed using materials selected from the group consisting of naturalgelatin, synthetic gelatin, pectin, casein, collagen, protein, modifiedstarch, polyvinylpyrrolidone, acrylic polymers, cellulose derivatives,and any combinations thereof.

In some embodiments, the pharmaceutical composition is free ofadditional excipients. In some embodiments, the pharmaceuticalcomposition further comprises one or more pharmaceutically acceptableexcipients. In some embodiments, the pharmaceutical composition is inthe form of a tablet. In some embodiments, the pharmaceuticalcomposition further comprises one or more pharmaceutically acceptableexcipients.

In some embodiments, the pharmaceutical composition comprises betweenabout 1 mg and about 500 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises between about 5 mg and about 500 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition comprises betweenabout 10 mg and about 500 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises between about 10 mg and about 300mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesbetween about 10 mg and about 100 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 50mg and about 500 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 100 mg and about 400 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 100mg and about 300 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 150 mg and about 250 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof.

In some embodiments the pharmaceutical composition comprises about 400mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 300 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises about 250 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the pharmaceuticalcomposition comprises about 200 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises about 150 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition comprises about 80 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition comprises about 60mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 50 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises about 30 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the pharmaceutical composition provides a Compound1 T_(max) of about 2 to about 6 hours in a subject. In some embodiments,the pharmaceutical composition provides a Compound 1 T_(max) of about 3to about 5 hours in a subject. In some embodiments, the pharmaceuticalcomposition provides a Compound 1 T_(max) of about 6 hours in a subject.In some embodiments, the pharmaceutical composition provides a Compound1 T_(max) of about 5 hours in a subject. In some embodiments, thepharmaceutical composition provides a Compound 1 T_(max) of about 4hours in a subject. In some embodiments, the pharmaceutical compositionprovides a Compound 1 T_(max) of about 3 hours in a subject.

In some embodiments, the pharmaceutical composition is administered inthe fed state. In some embodiments, the pharmaceutical composition isadministered in the fasted state. In some embodiments, thepharmaceutical composition is administered once a day. In someembodiments, the pharmaceutical composition is administered twice a day.In some embodiments, the pharmaceutical composition is administeredthree times a day.

In some embodiments, the method further comprises administering aglucocorticoid. In some embodiments, the amount of glucocorticoidadministered is reduced as compared to a method not comprisingadministering Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the amount of glucocorticoid usedis reduced from a supraphysiologic amount to a physiologic amount. Insome embodiments, the amount of glucocorticoid is reduced by about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, or about 60%.

In some embodiments, the symptoms associated with high-doseglucocorticoid therapy are reduced. In some embodiments, the symptomsassociated with high-dose glucocorticoid therapy are obesity, insulinresistance, metabolic abnormalities, hypertension, cardiovasculardiseases, or osteoporosis. In some embodiments, the glucocorticoid isbeclomethasone, betamethasone, budesonide, cortisone, dexamethasone,hydrocortisone, methylprednisolone, prednisolone, prednisone, ortriamcinolone. In some embodiments, the glucocorticoid ishydrocortisone.

In some embodiments, the hydrocortisone is administered at a dose lessthan about 15 mg/day. In some embodiments, the hydrocortisone isadministered at a dose less than about 10 mg/day. In some embodiments,the hydrocortisone is administered at a dose less than about 5 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, and the glucocorticoid are administeredconcurrently. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered sequentially. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered sequentially within 24 hours. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, and the glucocorticoid are administered sequentiallywithin 8 hours. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered sequentially within 2 hours. In some embodiments, Compound1, or a pharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered sequentially within 30 minutes.

In some embodiments, the method further comprises administering amineralocorticoid. In some embodiments, the mineralocorticoid isfludrocortisone.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered at bedtime. In some embodiments,Compound 1, or a pharmaceutically acceptable salt or solvate thereof, isadministered less than about 4 hours before sleeping. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered less than about 2 hours beforesleeping. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered less than about 30mins before sleeping. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered inthe evening. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered at 10 pm at night.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered at or before the expected circadianrelease of adrenocorticotropic hormone (ACTH). In some embodiments,Compound 1, or a pharmaceutically acceptable salt or solvate thereof, isadministered about 3-4 hours before the expected circadian release ofadrenocorticotropic hormone (ACTH).

In some embodiments, CAH is classic CAH. In some embodiments, CAH isnon-classic CAH.

In some embodiments, the subject in need thereof is from about 12 yearsof age to about 20 years of age.

In one aspect, the present disclosure provides a method of improvinghyperandrogenic symptoms in a subject in need thereof, comprisingadministering a pharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day. In some embodiments, the hyperandrogenic symptoms areselected from the group consisting of acne, hirsutism and alopecia.

In one aspect, the present disclosure provides a method of treatingmenstrual irregularity, ovulatory dysfunction or infertility, in asubject in need thereof, comprising administering a pharmaceuticalcomposition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day.

In one aspect, the present disclosure provides a method of improvingmetabolic symptoms in a subject in need thereof, comprisingadministering a pharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day. In some embodiments, the metabolic symptoms are selectedfrom the group consisting of body weight, BMI, waist circumference,blood pressure and glycemic control.

In one aspect, the present disclosure provides a method of improvingquality of life in a subject in need thereof, comprising administering apharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day, wherein treatment results in an improved quality of life.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 shows Compound 1 in patients with CAH following 14-days of oncedaily dosing at each level;

FIG. 2 demonstrates the attenuation of ACTH across different subjectsdue to the administration of Compound 1;

FIG. 3 demonstrates the reduction in 17-OHP due to the administration ofCompound 1;

FIG. 4 demonstrates the reduction of Androstenedione due to theadministration of Compound.

DETAILED DESCRIPTION OF THE INVENTION

CRF has been implicated in psychiatric disorders and neurologicaldiseases including depression and anxiety, as well as the following:Alzheimer's disease, Huntington's disease, progressive supranuclearpalsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy,migraine, alcohol and substance abuse and associated withdrawalsymptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia(CAH), Cushing's disease, hypertension, stroke, irritable bowelsyndrome, stress-induced gastric ulceration, premenstrual syndrome,sexual dysfunction, premature labor, inflammatory disorders, allergies,multiple sclerosis, visceral pain, sleep disorders, pituitary tumors orectopic pituitary derived tumors, chronic fatigue syndrome, andfibromyalgia.

CRF receptor subtypes, CRF1 and CRF2, have been identified and aredistributed heterogeneously within the brain thereby suggestingpotential functional diversity. For example, widely distributed brainCRF1 receptors are strongly implicated in emotionality accompanyingexposure to environmental stressors. Significantly, CRF1, not CRF2,receptors appear to mediate select anxiogenic like behaviors. A morediscrete septallhypothalmic distribution and the availability ofalternative endogenous ligands suggest a different functional role forthe CRF2 receptor. For example, a novel CRF-family neuropeptide withpreferential affinity for CRF2 relative to CRF 1 receptors is reportedto suppress appetite without producing the profile of behavioralactivation observed with selective CRF1 agonism. In other cases, CRF2agonism produces similar effects to those reported for CRF 1 antagonistsor CRF 1 gene deletion. For example, while CRF2 agonists have beenproposed as antiobesity agents, CRF1 antagonists may be an importanttreatment for obesity as well.

Treatment of CAH is based on normalization of hormone and steroid levelsusing a variety of medications from diagnosis in infancy throughadulthood. Glucocorticoids are the current standard treatment in CAH andare used both to correct the endogenous Cortisol deficiency and forreducing the elevated ACTH levels from the pituitary, which drivesincreased androgen production. Unlike the treatment of Addison's disease(adrenal insufficiency), in which Cortisol replacement is sufficient,the treatment of CAH must also reduce ACTH production, to control thesubsequent androgen excess as well. Thus, the goals of glucocorticoidtreatment include Cortisol replacement and suppression of ACTH toprevent virilization and menstrual disturbances in women.Mineralocorticoid replacement is needed to achieve normal plasma reninactivity for maintenance of regular blood pressure, electrolyte balance,and volume status in those patients with the salt-wasting form of CAH.

The regimen of glucocorticoid treatment must support normal physiologyand also ensure that sufficient Cortisol is available during events thatmay elicit a strong stress response (e.g., intercurrent illness,exercise, hypotension). Careful monitoring is also necessary to avoidthe development of Addisonian syndrome due to under-treatment.Overtreatment with mineralocorticoids may cause hypertension whileunder-treatment may lead to low blood pressure, salt loss, fatigue andincreased requirements for glucocorticoids. Typical laboratory tests formonitoring treatment efficacy include measurement of plasmaconcentrations of 17-OHP, androstenedione, testosterone, renin activity,and electrolytes.

Adult patients with CAH have an increased prevalence of risk factors forcardiovascular disease including obesity, hypertension, and insulinresistance. A study of a large cohort of pediatric and adult CAHpatients (n=244) demonstrated that patients are prescribed a variety ofglucocorticoid treatment regimens yet frequently suffer from poorhormonal control and the aforementioned adverse outcomes. Treatment ofCAH includes efforts to normalize the Cortisol deficiency withglucocorticoids (usually hydrocortisone in children but often morepotent agents with narrow therapeutic indices, such as dexamethasone, inadults) and, if necessary for salt-wasting, mineralocorticoids (usuallyfludrocortisone). The glucocorticoid doses required to achievesufficient suppression of excess androgens, however, are usually wellabove the normal physiologic dose used for Cortisol replacement alone asin patients with Addison's disease. This increased exposure toglucocorticoids can lead to increased cardiovascular risk factors,glucose intolerance, and decreased bone mineral density in CAH patients.

CRF is believed to be the major physiological regulator of the basal andstress-induced release of adrenocorticotropic hormone (“ACTH”),β-endorphin, and other proopiomelanocortin (“POMC”)-derived peptidesfrom the anterior pituitary. Secretion of CRF causes release of ACTHfrom corticotrophs in the anterior pituitary via binding to the CRF₁receptor, a member of the class B family of G-protein coupled receptors.

Due to the physiological significance of CRF₁, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF₁ receptorremains a desirable goal and has been the subject of ongoing researchand development for the treatment of anxiety, depression, irritablebowel syndrome, post-traumatic stress disorder, and substance abuse.

The pituitary hormone ACTH, under the control of hypothalamiccorticotropin-releasing factor (CRF), stimulates uptake of cholesteroland drives the synthesis of pregnenolone initiating steroidogenesis inthe adrenal gland. The adrenal cortex is comprised of three zones, whichproduce distinct classes of hormones many of which are driven by ACTHmobilizing cholesterol through this pathway. Deficiencies in theseenzymes as a result of mutation or deletion cause the substrateconcentrations to increase. In the most common form of CAH resultingfrom mutations or deletions in the 21-hydroxylase gene (CYP21A2), potentandrogens are produced by the adrenal because of the accumulation of thesteroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP).Plasma levels of 17-OHP can reach 10-1000 times the normal concentrationin these cases. These increases result in the overproduction ofandrogens, specifically androstenedione, testosterone, anddihydroxytestosterone causing virilization in females. In addition,21-hydroxylase deficiency in CAH causes insufficient biosynthesis ofglucocorticoids and mineralocorticoids, specifically Cortisol andaldosterone. Cortisol is a critical negative feedback regulator ofhypothalamic CRF secretion and pituitary ACTH release. The lack ofglucocorticoid synthesis and release eliminates the restraint on thehypothalamus and pituitary, which causes ACTH levels to increase. Theexcessive ACTH stimulation causes hypertrophy of the zona fasciculataand zona reticularis resulting in adrenal hyperplasia.

In one embodiment, the CRF receptor antagonist useful for the treatmentof CAH is3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine.

Certain Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments described herein, certain preferred methods, devices, andmaterials are now described.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly dictatesotherwise. Thus, for example, reference to “an excipient” is a referenceto one or more excipients and equivalents thereof known to those skilledin the art, and so forth.

The term “about” is used to indicate that a value includes the standardlevel of error for the device or method being employed to determine thevalue.

The use of the term “or” in the claims is used to mean “and/or” unlessexplicitly indicated to refer to alternatives only or the alternativesare mutually exclusive, although the disclosure supports a definitionthat refers to only alternatives and to “and/or.”

The terms “comprise,” “have” and “include” are open-ended linking verbs.Any forms or tenses of one or more of these verbs, such as “comprises,”“comprising,” “has,” “having,” “includes” and “including,” are alsoopen-ended. For example, any method that “comprises,” “has” or“includes” one or more steps is not limited to possessing only those oneor more steps and also covers other unlisted steps.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic systemically or locally, as directly into oronto a target tissue, or to administer a therapeutic to a patientwhereby the therapeutic positively impacts the tissue to which it istargeted. “Administering” a pharmaceutical composition may beaccomplished by injection, topical administration, and oraladministration or by other methods alone or in combination with otherknown techniques.

By “pharmaceutically acceptable”, it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of thecomposition and not deleterious to the recipient thereof.

The term “pharmaceutical composition” means a composition comprising atleast one active ingredient, such as Compound 1, whereby the compositionis amenable to investigation for a specified, efficacious outcome in amammal (for example, without limitation, a human). Those of ordinaryskill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

The term “supraphysiologic” amount” describes hormones levels that areelevated compared to average levels found in healthy individuals.

The term “physiologic amount” describes average hormone levels found inhealthy individuals.

A “therapeutically effective amount” or “effective amount” as usedherein refers to the amount of active compound or pharmaceutical agentthat elicits a biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician, which includes one ormore of the following: (1) preventing the disease; for example,preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display the pathology or symptomatology of the disease,(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and (3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The terms “treat,” “treated,” “treatment,” or “treating” as used hereinrefers to both therapeutic treatment in some embodiments andprophylactic or preventative measures in other embodiments, wherein theobject is to prevent or slow (lessen) an undesired physiologicalcondition, disorder or disease, or to obtain beneficial or desiredclinical results. For the purposes described herein, beneficial ordesired clinical results include, but are not limited to, alleviation ofsymptoms; diminishment of the extent of the condition, disorder ordisease; stabilization (i.e., not worsening) of the state of thecondition, disorder or disease; delay in onset or slowing of theprogression of the condition, disorder or disease; amelioration of thecondition, disorder or disease state; and remission (whether partial ortotal), whether detectable or undetectable, or enhancement orimprovement of the condition, disorder or disease. Treatment includeseliciting a clinically significant response without excessive levels ofside effects. Treatment also includes prolonging survival as compared toexpected survival if not receiving treatment. A prophylactic benefit oftreatment includes prevention of a condition, retarding the progress ofa condition, stabilization of a condition, or decreasing the likelihoodof occurrence of a condition. As used herein, “treat,” “treated,”“treatment,” or “treating” includes prophylaxis in some embodiments.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

Compound

Disclosed herein is3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidine(or alternatively4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholine),a pharmaceutically acceptable salt, and/or a solvate thereof:

In some embodiments,4-(4-chloro-5-(2,5-dimethyl-7-(pentan-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)thiazol-2-yl)morpholineis referred to as Compound 1. In some embodiments,3-(4-Chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(1-ethylpropyl)-2,5-dimethylpyrazolo(1,5-a)pyrimidineis referred to as Compound 1.

Pharmaceutical Compositions

Disclosed herein is a pharmaceutical composition comprising Compound 1,a pharmaceutically acceptable salt, and/or a solvate thereof.

Dosage Form

In some embodiments, the pharmaceutical compositions described hereinare provided in unit dosage form. As used herein, a “unit dosage form”is a composition containing an amount of Compound 1 that is suitable foradministration to an animal, preferably mammal, subject in a singledose, according to good medical practice. The preparation of a single orunit dosage form however, does not imply that the dosage form isadministered once per day or once per course of therapy. Such dosageforms are contemplated to be administered once, twice, thrice or moreper day and may be administered as infusion over a period of time (e.g.,from about 30 minutes to about 2-6 hours), or administered as acontinuous infusion, and may be given more than once during a course oftherapy, though a single administration is not specifically excluded.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. The optimal dose dependsupon the body mass, weight, or blood volume of the patient.

In some embodiments, the pharmaceutical compositions described hereinare formulated as oral dosage forms. Suitable oral dosage forms include,for example, tablets, pills, sachets, or capsules. In some embodiments,the pharmaceutical composition comprises one or more additionalpharmaceutically acceptable excipients. See, e.g., Remington: TheScience and Practice of Pharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co.,Easton, PA (2005) for a list of pharmaceutically acceptable excipients.

Capsule

In some embodiments, the pharmaceutical composition is formulated as acapsule. In some embodiments, the pharmaceutical composition isformulated as a hard gel capsule. In some embodiments, thepharmaceutical composition is formulated as a soft gel capsule.

In some embodiments, the capsule is formed using materials whichinclude, but are not limited to, natural or synthetic gelatin, pectin,casein, collagen, protein, modified starch, polyvinylpyrrolidone,acrylic polymers, cellulose derivatives, or any combinations thereof. Insome embodiments, the capsule is formed using preservatives, coloringand opacifying agents, flavorings and sweeteners, sugars,gastroresistant substances, or any combinations thereof. In someembodiments, the capsule is coated. In some embodiments, the coatingcovering the capsule includes, but is not limited to, immediate releasecoatings, protective coatings, enteric or delayed release coatings,sustained release coatings, barrier coatings, seal coatings, orcombinations thereof. In some embodiments, a capsule herein is hard orsoft. In some embodiments, the capsule is seamless. In some embodiments,the capsule is broken such that the particulates are sprinkled on softfoods and swallowed without chewing. In some embodiments, the shape andsize of the capsule also vary. Examples of capsule shapes include, butare not limited to, round, oval, tubular, oblong, twist off, or anon-standard shape. The size of the capsule may vary according to thevolume of the particulates. In some embodiments, the size of the capsuleis adjusted based on the volume of the particulates and powders. Hard orsoft gelatin capsules may be manufactured in accordance withconventional methods as a single body unit comprising the standardcapsule shape. A single-body soft gelatin capsule typically may beprovided, for example, in sizes from 3 to 22 minims (1 minims beingequal to 0.0616 ml) and in shapes of oval, oblong or others. The gelatincapsule may also be manufactured in accordance with conventionalmethods, for example, as a two-piece hard gelatin capsule, sealed orunsealed, typically in standard shape and various standard sizes,conventionally designated as (000), (00), (0), (1), (2), (3), (4), and(5). The largest number corresponds to the smallest size. In someembodiments, the pharmaceutical composition described herein (e.g.,capsule) is swallowed as a whole.

In some embodiments, the capsule comprises one or more pharmaceuticallyacceptable excipients. In some embodiments, the capsule is free ofadditional excipients.

In some embodiments, a capsule is developed, manufactured andcommercialized for a drug substance that is insoluble. In someembodiments, a drug substance is insoluble if solubility is less than0.002 mg/mL in water. In some embodiments, the capsule has a dosestrength of up to 200 mg. In some embodiments, drug substance in thecapsule is immediately released in a dissolution medium using USPapparatus I. In some embodiments, drug substance in the capsule isimmediately released in a dissolution medium using USP apparatus II.

Tablet

Poorly soluble drugs may be difficult to formulate using standardtechnologies such as high shear wet granulation. Optimum delivery ofpoorly soluble drugs may require complex technologies such as solidsolutions amorphous dispersions (hot melt extrusion or spray drying),nano-formulations or lipid-based formulations. Hydrophobic drugsubstances may be considered poorly soluble according to USP criteriaand may be known to be difficult to granulate with water and otherexcipients. This is likely due to most known excipients for immediaterelease formulations being water soluble or water-swellable. Making atablet of a high dose drug substance that is poorly soluble may requirea high concentration of the drug substance. However, as the drugconcentration is increased above a certain level, formation of granulesmay become more and more difficult. Furthermore, at a certain drug load,it may become impossible.

In some embodiments, the pharmaceutical composition is formulated as atablet.

In some embodiments, the tablet is made by compression, molding, orextrusion, optionally with one or more pharmaceutically acceptableexcipient. In some embodiments, compressed tablets are prepared bycompressing Compound 1 in a free-flowing form, optionally mixed withpharmaceutically acceptable excipients. In some embodiments, moldedtablets are made by molding a mixture of the powdered Compound 1moistened with an inert liquid diluent. In some embodiments, the tabletis prepared by hot-melt extrusion. In some embodiments, extruded tabletsare made by forcing a mixture comprising Compound 1 through an orificeor die under controlled conditions. In some embodiments, the tablet iscoated or scored. In some embodiments, the tablet is formulated so as toprovide slow or controlled release of Compound 1. In some embodiments, atablet is developed, manufactured and commercialized for a drugsubstance that is insoluble. In some embodiments, a drug substance isinsoluble if solubility is less than 0.002 mg/mL in water. In someembodiments, the tablet has a dose strength of up to 200 mg. In someembodiments, drug substance in the tablet is immediately released in adissolution medium using USP apparatus I. In some embodiments, drugsubstance in the tablet is immediately released in a dissolution mediumusing USP apparatus II.

In some embodiments, the tablet size is less than about 1000 mg, lessthan about 800 mg, less than about 600 mg, less than about 400 mg orless than about 200 mg. In some embodiments, the tablet has a dosestrength of more than about 50 mg, more than about 100 mg, more thanabout 150 mg, more than about 200 mg, or more than about 250 mg. In someembodiments, the tablet size is less than about 1000 mg for a dosestrength of more than about 50 mg. In some embodiments, the tablet sizeis less than 800 mg for a dose strength of more than about 100 mg. Insome embodiments, the tablet size is less than 600 mg for a dosestrength of more than about 150 mg. In some embodiment, the tablet sizeis less than 400 mg for a dose strength of more than about 200 mg. Insome embodiments, the tablet size is less than 400 mg for a dosestrength of 200 mg.

In some embodiments, more than about 20% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 40%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 50% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 60%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 70% of the tablet is dissolved inconventional dissolution media. In some embodiments, more than about 80%of the tablet is dissolved in conventional dissolution media. In someembodiments, more than about 20% of the tablet is dissolved in less than24 hours in conventional dissolution media. In some embodiments, morethan about 20% of the tablet is dissolved in less than 12 hours inconventional dissolution media. In some embodiments, more than about 20%of the tablet is dissolved in less than 6 hours in conventionaldissolution media. In some embodiments, more than about 20% of thetablet is dissolved in less than 3 hours in conventional dissolutionmedia. In some embodiments, more than about 20% of the tablet isdissolved in less than 2 hours in conventional dissolution media. Insome embodiments, more than about 20% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than about 40% of the tablet is dissolved in less than 60 minutesin conventional dissolution media. In some embodiments, more than about50% of the tablet is dissolved in less than 60 minutes in conventionaldissolution media. In some embodiments, more than about 60% of thetablet is dissolved in less than 60 minutes in conventional dissolutionmedia. In some embodiments, more than about 70% of the tablet isdissolved in less than 60 minutes in conventional dissolution media. Insome embodiments, more than about 80% of the tablet is dissolved in lessthan 60 minutes in conventional dissolution media. In some embodiments,more than 70% of the tablet is dissolved in 60 minutes in conventionaldissolution media.

In some embodiments, the tablet is produced at a commercial scale.

In some embodiments, the tablet comprises one or more pharmaceuticallyacceptable excipients.

In some embodiments, the tablet is coated with a coating material, e.g.,a sealant. In some embodiments, the coating material is water soluble.In some embodiments, the coating material comprises a polymer,plasticizer, a pigment, or any combination thereof. In some embodiments,the coating material is in the form of a film coating, e.g., a glossyfilm, a pH independent film coating, an aqueous film coating, a drypowder film coating (e.g., complete dry powder film coating), or anycombination thereof. In some embodiments, the coating material is highlyadhesive. In some embodiments, the coating material provides low levelof water permeation. In some embodiments, the coating material providesoxygen barrier protection. In some embodiments, the coating materialallows immediate disintegration for fast release of Compound 1. In someembodiments, the coating material is pigmented, clear, or white. In someembodiments, the coating is an enteric coating. Exemplary coatingmaterials include, without limitation, polyvinylpyrrolidone, polyvinylalcohol, an acrylate-methacrylic acid copolymer, amethacrylate-methacrylic acid copolymer, cellulose acetate phthalate,cellulose acetate succinate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, shellac, cellulose acetate trimellitate, sodium alginate,zein, and any combinations thereof.

Pharmaceutically Acceptable Excipients

In some embodiments, the pharmaceutical composition comprises apharmaceutically acceptable excipient. In some embodiments, thecomposition is free of pharmaceutically acceptable excipients. The term“pharmaceutically acceptable excipient”, as used herein, means one ormore compatible solid or encapsulating substances, which are suitablefor administration to a mammal. The term “compatible”, as used herein,means that the components of the composition are capable of beingcommingled with the subject compound, and with each other, in a mannersuch that there is no interaction, which would substantially reduce thepharmaceutical efficacy of the composition under ordinary usesituations. In some embodiments, the pharmaceutically acceptableexcipient is of sufficiently high purity and sufficiently low toxicityto render them suitable for administration preferably to an animal,preferably mammal, being treated.

Some examples of substances, which can serve as pharmaceuticallyacceptable excipients include:

-   -   Amino acids such as alanine, arginine, asparagine, aspartic        acid, cysteine, glutamine, glutamic acid, glycine, histidine,        isoleucine, leucine, lysine, methionine, phenylalanine, proline,        serine, threonine, tryptophan, tyrosine, and valine. In some        embodiments, the amino acid is arginine. In some embodiments,        the amino acid is L-arginine.    -   Monosaccharides such as glucose (dextrose), arabinose, mannitol,        fructose (levulose), and galactose.    -   Cellulose and its derivatives such as sodium carboxymethyl        cellulose, ethyl cellulose, and methyl cellulose.    -   Solid lubricants such as talc, stearic acid, magnesium stearate,        and sodium stearyl fumarate.    -   Polyols such as propylene glycol, glycerin, sorbitol, mannitol,        and polyethylene glycol.    -   Emulsifiers such as the polysorbates.    -   Wetting agents such as sodium lauryl sulfate, Tween®, Span,        alkyl sulphates, and alkyl ethoxylate sulphates.    -   Diluents such as calcium carbonate, microcrystalline cellulose,        calcium phosphate, starch, pregelatinized starch, sodium        carbonate, mannitol, and lactose.    -   Binders such as starches (corn starch and potato starch),        gelatin, sucrose, hydroxypropyl cellulose (HPC),        polyvinylpyrrolidone (PVP), and hydroxypropyl methyl cellulose        (HPMC).    -   Disintegrants such as starch, and alginic acid.    -   Super-disintegrants such as ac-di-sol, croscarmellose sodium,        sodium starch glycolate and crospovidone.    -   Glidants such as silicon dioxide.    -   Coloring agents such as the FD&C dyes.    -   Sweeteners and flavoring agents, such as aspartame, saccharin,        menthol, peppermint, and fruit flavors.    -   Preservatives such as benzalkonium chloride, PHMB,        chlorobutanol, thimerosal, phenylmercuric, acetate,        phenylmercuric nitrate, parabens, and sodium benzoate.    -   Tonicity adjustors such as sodium chloride, potassium chloride,        mannitol, and glycerin.    -   Antioxidants such as sodium bisulfite, acetone sodium bisulfite,        sodium formaldehyde, sulfoxylate, thiourea, and EDTA.    -   pH adjuster such as NaOH, sodium carbonate, sodium acetate, HCl,        and citric acid.    -   Cryoprotectants such as sodium or potassium phosphates, citric        acid, tartaric acid, gelatin, and carbohydrates such as        dextrose, mannitol, and dextran.    -   Cationic surfactants such as cetrimide, benzalkonium chloride        and cetylpyridinium chloride.    -   Anion surfactants such as alkyl sulphates, alkyl ethoxylate        sulphates, soaps, carboxylates, sulfates, and sulfonates.    -   Non-ionic surfactants such as polyoxyethylene derivatives,        polyoxypropylene derivatives, polyol derivatives, polyol esters,        polyoxyethylene esters, poloxamers, glyol esters, glycerol        esters, sorbitan derivatives, polyethylene glycol (PEG-40,        PEG-50, PEG-55), and ethers of fatty alcohols.    -   Organic materials such as carbohydrate and modified        carbohydrates, lactose, a-lactose monohydrate, spray dried        lactose and anhydrous lactose, starch and pre-gelatinized        starch, sucrose, manitol, sorbitol, cellulose, powdered        cellulose and microcrystalline cellulose.    -   Inorganic materials such as calcium phosphates (anhydrous        dibasic calcium phosphate, dibasic calcium phosphate and        tribasic calcium phosphate).    -   Co-processed diluents.    -   Surfactants such as sodium lauryl sulfate.    -   Compression aids.    -   Anti-tacking agents such as silicon dioxide and talc

Amounts

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 60 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 50 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 40 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 30 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 20 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 10 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 5 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule comprises about 1 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition, in the form of a tablet orcapsule comprises about 5 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 1 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 5 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 10 mg and about 60 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 20 mg and about 60 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 30 mg and about 60 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 40 mg and about 60 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises about 50 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 500 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 400 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 300 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 200 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 100 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 90 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 80 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition, in the form of atablet or capsule, comprises between about 50 mg and about 70 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition comprises betweenabout 100 mg and about 500 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises between about 100 mg and about 400mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesbetween about 100 mg and about 300 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises between about 150mg and about 250 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof. In some embodiments, the pharmaceutical compositioncomprises between about 100 mg and about 200 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, the pharmaceutical composition comprises about 500mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 400 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises about 300 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the pharmaceuticalcomposition comprises about 250 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises about 200 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises about 150 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition comprises about 100 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition comprises about 90mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 80 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the pharmaceutical compositioncomprises about 70 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the pharmaceuticalcomposition comprises about 60 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, thepharmaceutical composition comprises about 50 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof. In someembodiments, the pharmaceutical composition comprises about 40 mg ofCompound 1, or a pharmaceutically acceptable salt or solvate thereof. Insome embodiments, the pharmaceutical composition comprises about 30 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, the pharmaceutical composition comprises about 20mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof. In some embodiments, the pharmaceutical composition comprisesabout 10 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof.

Particle Size

In some embodiments, the pharmaceutical composition, in the form of atablet or a capsule, comprises Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, in the form of microparticles. Insome embodiments, microparticles of Compound 1 have an average size fromabout 1 μm to about 100 μm. In some embodiments, microparticles ofCompound 1 have an average size from about 1 μm to about 50 μm. In someembodiments, microparticles of Compound 1 have an average size fromabout 1 μm to about 30 μm. In some embodiments, microparticles ofCompound 1 have an average size from about 1 μm to about 20 μm. In someembodiments, microparticles of Compound 1 have an average size fromabout 5 μm to about 15 μm. In some embodiments, microparticles ofCompound 1 have an average size from about 1 μm to about 10 μm. In someembodiments, microparticles of Compound 1 have an average size fromabout 3 μm to about 10 μm. In some embodiments, microparticles ofCompound 1 have an average size from about 4 μm to about 9 μm.

In some embodiments, microparticles of Compound 1 have an average sizeless than about 100 μm. In some embodiments, microparticles of Compound1 have an average size less than about 80 μm. In some embodiments,microparticles of Compound 1 have an average size less than about 60 μm.In some embodiments, microparticles of Compound 1 have an average sizeless than about 50 μm. In some embodiments, microparticles of Compound 1have an average size less than about 40 μm. In some embodiments,microparticles of Compound 1 have an average size less than about 30 μm.In some embodiments, microparticles of Compound 1 have an average sizeless than about 20 μm. In some embodiments, microparticles of Compound 1have an average size less than about 10 μm.

Pharmacokinetics

In some embodiments, Compound 1 is formulated as a capsule or a tabletas to provide a Tmax of about 1 to about 8 hours in a subject. In someembodiments, Compound 1 is formulated as a capsule or a tablet as toprovide a Tmax of about 2 to about 7 hours in a subject. In someembodiments, Compound 1 is formulated as a capsule or a tablet as toprovide a Tmax of about 2 to about 6 hours in a subject. In someembodiments, Compound 1 is formulated as a capsule or a tablet as toprovide a Tmax of about 3 to about 5 hours in a subject.

In some embodiments, Compound 1 is formulated as a capsule or a tabletas to provide a Tmax of about 8 hours in a subject. In some embodiments,Compound 1 is formulated as a capsule or a tablet as to provide a Tmaxof about 7 hours in a subject. In some embodiments, Compound 1 isformulated as a capsule or a tablet as to provide a Tmax of about 6hours in a subject. In some embodiments, Compound 1 is formulated as acapsule or a tablet as to provide a Tmax of about 5 hours in a subject.In some embodiments, Compound 1 is formulated as a capsule or a tabletas to provide a Tmax of about 4 hours in a subject. In some embodiments,Compound 1 is formulated as a capsule or a tablet as to provide a Tmaxof about 3 hours in a subject. In some embodiments, Compound 1 isformulated as a capsule or a tablet as to provide a Tmax of about 2hours in a subject. In some embodiments, Compound 1 is formulated as acapsule or a tablet as to provide a Tmax of about 1 hour in a subject.

Stability

The pharmaceutical compositions described herein are stable in variousstorage conditions including refrigerated, ambient and acceleratedconditions. Stable as used herein refers to pharmaceutical compositionshaving about 95% or greater of the initial Compound 1 amount and about5% w/w or less total impurities or related substances at the end of agiven storage period. The percentage of impurities is calculated fromthe amount of impurities relative to the amount of Compound 1. Stabilityis assessed by HPLC or any other known testing method. In someembodiments, the stable pharmaceutical compositions have about 5% w/w,about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5%w/w, about 1% w/w, or about 0.5% w/w total impurities or relatedsubstances. In other embodiments, the stable pharmaceutical compositionshave about 5% w/w total impurities or related substances. In yet otherembodiments, the stable pharmaceutical compositions have about 4% w/wtotal impurities or related substances. In yet other embodiments, thestable pharmaceutical compositions have about 3% w/w total impurities orrelated substances. In yet other embodiments, the stable pharmaceuticalcompositions have about 2% w/w total impurities or related substances.In yet other embodiments, the stable pharmaceutical compositions haveabout 1% w/w total impurities or related substances.

At refrigerated condition, the pharmaceutical compositions describedherein are stable for at least 1 month, at least 2 months, at least 3months, at least 6 months, at least 9 months, at least 12 months, atleast 15 months, at least 18 months, at least 24 months, at least 30months and at least 36 months. In some embodiments, refrigeratedcondition is 5±5° C. In some embodiments, refrigerated condition isabout 0° C., about 0.1° C., about 0.2° C., about 0.3° C., about 0.4° C.,about 0.5° C., about 0.6° C., about 0.7° C., about 0.8° C., about 0.9°C., about 1° C., about 1.1° C., about 1.2° C., about 1.3° C., about 1.4°C., about 1.5° C., about 1.6° C., about 1.7° C., about 1.8° C., about1.9° C., about 2° C., about 2.1° C., about 2.2° C., about 2.3° C., about2.4° C., about 2.5° C., about 2.6° C., about 2.7° C., about 2.8° C.,about 2.9° C., about 3° C., about 3.1° C., about 3.2° C., about 3.3° C.,about 3.4° C., about 3.5° C., about 3.6° C., about 3.7° C., about 3.8°C., about 3.9° C., about 4° C., about 4.1° C., about 4.2° C., about 4.3°C., about 4.4° C., about 4.5° C., about 4.6° C., about 4.7° C., about4.8° C., about 4.9° C., about 5° C., about 5.1° C., about 5.2° C., about5.3° C., about 5.4° C., about 5.5° C., about 5.6° C., about 5.7° C.,about 5.8° C., about 5.9° C., about 6° C., about 6.1° C., about 6.2° C.,about 6.3° C., about 6.4° C., about 6.5° C., about 6.6° C., about 6.7°C., about 6.8° C., about 6.9° C., about 7° C., about 7.1° C., about 7.2°C., about 7.3° C., about 7.4° C., about 7.5° C., about 7.6° C., about7.7° C., about 7.8° C., about 7.9° C., about 8° C., about 8.1° C., about8.2° C., about 8.3° C., about 8.4° C., about 8.5° C., about 8.6° C.,about 8.7° C., about 8.8° C., about 8.9° C., about 9° C., about 9.1° C.,about 9.2° C., about 9.3° C., about 9.4° C., about 9.5° C., about 9.6°C., about 9.7° C., about 9.8° C., about 9.9° C., or about 10° C. Ataccelerated conditions, the pharmaceutical compositions described hereinare stable for at least 1 month, at least 2 months, at least 3 months,at least 4 months, at least 5 months, at least 6 months, at least 7months, at least 8 months, at least 9 months, at least 10 months, atleast 11 months, at least 12 months, at least 18 months, or at least 24month. Accelerated conditions for the pharmaceutical compositionsdescribed herein include temperatures that are at or above ambientlevels (e.g. 25±5° C.). In some instances, an accelerated condition isat about 40±2° C. In some instances, an accelerated condition is atabout 35° C., about 40° C., about 45° C., about 50° C., about 55° C., orabout 60° C. Accelerated conditions for the pharmaceutical compositionsdescribed herein also include relative humidity (RH) that are at orabove ambient levels (55±10% RH). In other instances, an acceleratedcondition is above about 65% RH, about 70% RH, about 75% RH, or about80% RH. In further instances, an accelerated condition is about 40° C.or 60° C. at ambient humidity. In yet further instances, an acceleratedcondition is about 40±2° C. at 75±5% RH humidity.

In some embodiments, the pharmaceutical compositions are stable at about5±5° C. to about 25±5° C. for at least 12 months. In one embodiment, thepharmaceutical compositions are stable at about 5±5° C. for at least 12months. In one embodiment, the pharmaceutical compositions are stable atabout 25±5° C. for at least 12 months. In one embodiment, thepharmaceutical compositions are stable at about 5±5° C. for at least 24months. In one embodiment, the pharmaceutical compositions are stable atabout 25±5° C. for at least 24 months.

Methods of Use

Disclosed herein is a method of treating congenital adrenal hyperplasia(CAH) in a subject in need thereof, comprising administering apharmaceutical composition comprising Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, CAH is classicCAH. In some embodiments, CAH is non-classic CAH. In some embodiments,the methods described herein result in the reduction of a hormone level.Such hormones include deoxycorticosterone, 11-deoxycortisol, cortisol,corticosterone, aldosterone, pregnenolone, 17α-hydroxy pregnenolone,progesterone, 17α-hydroxy progesterone (17-OHP), dehydroepiandrosterone,androstenediol, androstenedione, testosterone, dihydrotestosterone,estrone, estradiol, estriol, and adrenocorticotropic hormone (ACTH). Insome embodiments, the methods described herein result in the reductionof 17α-hydroxy progesterone (17-OHP). In some embodiments, the methodsdescribed herein result in the reduction of adrenocorticotropic hormone(ACTH), also known as corticotropin.

Also disclosed herein is a method of treating congenital adrenalhyperplasia (CAH) in a subject in need thereof, the method comprising:

-   -   (i) measuring a hormone level in the subject in need thereof;    -   (ii) administering Compound 1:

or a pharmaceutically acceptable salt or solvate thereof;

-   -   (iii) repeating steps (i) and (ii) until the hormone level        reaches a pre-determined range followed by a maintenance therapy        of a daily dosing of compound 1.

In some embodiment, the hormone is 17α-Hydroxyprogesterone (17-OHP),adrenocorticotropic hormone (ACTH), testosterone, or androstenedione.

In some embodiment, the hormone is 17-OHP, and the pre-determined rangeis from about 200 ng/dL to about 400 ng/dL. In some embodiment, thehormone is 17-OHP, and the pre-determined range is less than about 400ng/dL, less than about 350 ng/dL, less than about 300 ng/dL, less thanabout 250 ng/dL, or less than about 200 ng/dL.

In some embodiment, the hormone is ACTH, and the pre-determined range isbelow about 100 pg/mL. In some embodiment, the hormone is ACTH, and thepre-determined range is below about 100 pg/mL, below about 90 pg/mL, orbelow about 80 pg/mL.

In some embodiment, the hormone is testosterone and the pre-determinedrange is from about 14 ng/dL to about 76 ng/dL. In some embodiment, thehormone is testosterone and the pre-determined range is less than about76 ng/dL, less than about 70 ng/dL, less than about 65 ng/dL, less thanabout 60 ng/dL, less than about 55 ng/dL, less than about 50 ng/dL, lessthan about 45 ng/dL, less than about 40 ng/dL, less than about 35 ng/dL,less than about 30 ng/dL, less than about 25 ng/dL, less than about 20ng/dL, or less than about 15 ng/dL.

In some embodiment, the hormone is androstenedione and thepre-determined range is from about 30 ng/dL to about 200 ng/dL in males.In some embodiment, the hormone is androstenedione and thepre-determined range is less than about 200 ng/dL, less than about 150ng/dL, less than about 100 ng/dL, less than about 50 ng/dL, or less thanabout 30 ng/dL in males.

In some embodiment, the hormone is androstenedione and thepre-determined range is from about 40 ng/dL to about 150 ng/dL infemales. In some embodiment, the hormone is androstenedione and thepre-determined range is less about 150 ng/dL, less about 100 ng/dL, lessabout 50 ng/dL, or less about 40 ng/dL in females.

In some embodiments, the methods described herein include administrationof the pharmaceutical composition comprising Compound 1, or apharmaceutically acceptable salt or solvate thereof once a month, twicea month, three times a month, once a week, twice a week, three times aweek, once every two days, once a day, twice a day, three times a day,or four times a day. In some embodiments, the methods described hereinadminister Compound 1, or a pharmaceutically acceptable salt or solvatethereof once a day. In some embodiments, the methods described hereinadminister Compound 1, or a pharmaceutically acceptable salt or solvatethereof twice a day.

In some embodiments, the methods described herein include administrationof about 1 mg to about 2000 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, per day. In some embodiments,Compound 1 is administered at a dose between about 50 mg/day and about1600 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 50 mg/day and about 1500 mg/day. In some embodiments,Compound 1 is administered at a dose between about 50 mg/day and about1400 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 50 mg/day and about 1300 mg/day. In some embodiments,Compound 1 is administered at a dose between about 50 mg/day and about1200 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 50 mg/day and about 1100 mg/day. In some embodiments,Compound 1 is administered at a dose between about 50 mg/day and about1000 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 50 mg/day and about 900 mg/day. In some embodiments,Compound 1 is administered at a dose between about 50 mg/day and about800 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 60 mg/day and about 800 mg/day. In some embodiments,Compound 1 is administered at a dose between about 70 mg/day and about800 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 80 mg/day and about 800 mg/day. In some embodiments,Compound 1 is administered at a dose between about 90 mg/day and about800 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 100 mg/day and about 800 mg/day. In some embodiments,Compound 1 is administered at a dose between about 100 mg/day and about700 mg/day. In some embodiments, Compound 1 is administered at a dosebetween about 100 mg/day and about 600 mg/day. In some embodiments,Compound 1 is administered at a dose between 150 mg/day and about 600mg/day. In some embodiments, Compound 1 is administered at a dosebetween 200 mg/day and about 600 mg/day. In some embodiments, Compound 1is administered at a dose between 200 mg/day and about 500 mg/day. Insome embodiments, Compound 1 is administered at a dose between 200mg/day and about 400 mg/day.

In some embodiments, Compound 1 is administered at a dose of about 500mg/day. In some embodiments, Compound 1 is administered at a dose ofabout 400 mg/day. In some embodiments, Compound 1 is administered at adose of about 300 mg/day. In some embodiments, Compound 1 isadministered at a dose of about 200 mg/day. In some embodiments,Compound 1 is administered at a dose of about 100 mg/day.

In some embodiments, about 100 mg to about 1600 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, about 200 mg to about 1600 mg of Compound 1,or a pharmaceutically acceptable salt or solvate thereof, isadministered per day. In some embodiments, about 200 mg to about 1200 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof,is administered per day. In some embodiments, about 200 mg to about 1000mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof, is administered per day. In some embodiments, about 200 mg toabout 800 mg of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered per day. In some embodiments, about 100mg to about 800 mg of Compound 1, or a pharmaceutically acceptable saltor solvate thereof, is administered per day. In some embodiments, about200 mg to about 800 mg of Compound 1, or a pharmaceutically acceptablesalt or solvate thereof, is administered per day. In some embodiments,about 100 mg to about 600 mg of Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered per day. In someembodiments, about 200 mg to about 600 mg of Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, about 300 mg to about 600 mg of Compound 1, ora pharmaceutically acceptable salt or solvate thereof, is administeredper day. In some embodiments, about 100 mg to about 400 mg of Compound1, or a pharmaceutically acceptable salt or solvate thereof, isadministered per day. In some embodiments, about 200 mg to about 400 mgof Compound 1, or a pharmaceutically acceptable salt or solvate thereof,is administered per day. In some embodiments, about 300 mg to about 400mg of Compound 1, or a pharmaceutically acceptable salt or solvatethereof, is administered each day.

In some embodiments, less than about 2000 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1800 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1600 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1400 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1200 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 1000 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 800 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 600 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 500 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 400 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 300 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday. In some embodiments, less than about 200 mg Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered perday.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein wherein the subjectis in the fed state. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein wherein the subject is in the fasted state.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein at bedtime.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein less than about 4hours before sleep. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein less than about 3 hours before sleep. In some embodiments, themethods described herein include administration of the pharmaceuticalcompositions described herein less than about 2 hours before sleep. Insome embodiments, the methods described herein include administration ofthe pharmaceutical compositions described herein less than about 1 hourbefore sleep. In some embodiments, the methods described herein includeadministration of the pharmaceutical compositions described herein lessthan about 30 mins before sleep.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein in the evening.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein at about 11 pm atnight. In some embodiments, the methods described herein includeadministration of the pharmaceutical compositions described herein atabout 10 pm at night. In some embodiments, the methods described hereininclude administration of the pharmaceutical compositions describedherein at about 9 pm at night. In some embodiments, the methodsdescribed herein include administration of the pharmaceuticalcompositions described herein at about 8 pm at night.

In some embodiments, the methods described herein include administrationof the pharmaceutical compositions described herein at or before theexpected circadian release of adrenocorticotropic hormone (ACTH). Insome embodiments, the methods described herein include administration ofthe pharmaceutical compositions described herein about 3-4 hours beforethe expected circadian release of adrenocorticotropic hormone (ACTH). Insome embodiments, the subject in need thereof is from about 12 years ofage to about 20 years of age.

In one aspect, the present disclosure provides a method of improvinghyperandrogenic symptoms in a subject in need thereof, comprisingadministering a pharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day. In some embodiments, the hyperandrogenic symptoms areselected from the group consisting of acne, hirsutism and alopecia.

In one aspect, the present disclosure provides a method of treatingmenstrual irregularity, ovulatory dysfunction or infertility, in asubject in need thereof, comprising administering a pharmaceuticalcomposition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day.

In one aspect, the present disclosure provides a method of improvingmetabolic symptoms in a subject in need thereof, comprisingadministering a pharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day. In some embodiments, the metabolic symptoms are selectedfrom the group consisting of body weight, BMI, waist circumference,blood pressure and glycemic control.

In one aspect, the present disclosure provides a method of improvingquality of life in a subject in need thereof, comprising administering apharmaceutical composition comprising Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, whereinCompound 1 is administered at a dose between about 50 mg/day and about1600 mg/day, wherein treatment results in an improved quality of life.

Combination Therapy

Disclosed herein is a method of treating congenital adrenal hyperplasia(CAH) in a subject in need thereof, comprising administering acombination of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof and a glucocorticoid. In some embodiments, the amount ofglucocorticoid administered is reduced as compared to a method notcomprising administering Compound 1, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the methods described herein reduce the amount of aglucocorticoid administered from a supraphysiologic amount to aphysiologic amount.

In some embodiments, the methods described herein reduce the symptomsassociated with high-dose glucocorticoid therapy. In some embodiments,the symptoms associated with high-dose glucocorticoid therapy areobesity, insulin resistance, metabolic abnormalities, hypertension,cardiovascular diseases, or osteoporosis.

In some embodiments, the amount of glucocorticoid administered isreduced by about 5%, about 10%, about 15%, about 20%, about 25%, about30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%,about 65%, about 70%, about 80, or about 90% as compared to a method notcomprising administering Compound 1, or a pharmaceutically acceptablesalt or solvate thereof. In some embodiments, the amount ofglucocorticoid administered is reduced by about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, or about 60% as compared to a method notcomprising administering Compound 1, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the amount of glucocorticoid administered isreduced by about 1% to about 90%, about 1% to about 60%, about 1% toabout 30%, about 1% to about 10%, about 10% to about 50%, about 10% toabout 40%, about 10% to about 30%, about 15% to about 25%, about 20% toabout 30%, about 5% to about 25%, about 20% to about 50%, about 30% toabout 60%, or about 40% to about 70% as compared to a method notcomprising administering Compound 1, or a pharmaceutically acceptablesalt or solvate thereof.

In some embodiments, the glucocorticoid is administered at a dosebetween about 0.1 mg/day and about 25 mg/day. In some embodiments, theglucocorticoid is administered at a dose between about 1 mg/day andabout 20 mg/day. In some embodiments, the glucocorticoid is administeredat a dose between about 1 mg/day and about 15 mg/day. In someembodiments, the glucocorticoid is administered at a dose between about1 mg/day and about 12 mg/day. In some embodiments, the glucocorticoid isadministered at a dose between about 1 mg/day and about 11 mg/day. Insome embodiments, the glucocorticoid is administered at a dose betweenabout 1 mg/day and about 10 mg/day. In some embodiments, theglucocorticoid is administered at a dose between about 1 mg/day andabout 9 mg/day. In some embodiments, the glucocorticoid is administeredat a dose between about 1 mg/day and about 8 mg/day. In someembodiments, the glucocorticoid is administered at a dose between about1 mg/day and about 7 mg/day. In some embodiments, the glucocorticoid isadministered at a dose between about 1 mg/day and about 6 mg/day. Insome embodiments, the glucocorticoid is administered at a dose betweenabout 1 mg/day and about 5 mg/day. In some embodiments, theglucocorticoid is administered at a dose between about 1 mg/day andabout 4 mg/day. In some embodiments, the glucocorticoid is administeredat a dose between about 1 mg/day and about 3 mg/day. In someembodiments, the glucocorticoid is administered at a dose between about1 mg/day and about 2 mg/day. In some embodiments, the glucocorticoid isadministered at a dose between about 3 mg/day and about 13 mg/day. Insome embodiments, the glucocorticoid is administered at a dose betweenabout 5 mg/day and about 11 mg/day. In some embodiments, theglucocorticoid is administered at a dose between about 8 mg/day andabout 11 mg/day. In some embodiments, the glucocorticoid is administeredat a dose between about 9 mg/day and about 12 mg/day. In someembodiments, the glucocorticoid is administered at a dose between about9 mg/day and about 10 mg/day. In some embodiments, the glucocorticoid isadministered at a dose between about 5 mg/day and about 10 mg/day.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, and the glucocorticoid are administeredconcurrently. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered in one pharmaceutical composition. In some embodiments,Compound 1, or a pharmaceutically acceptable salt or solvate thereof,and the glucocorticoid are administered concurrently in separatepharmaceutical compositions.

In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, and the glucocorticoid are administeredsequentially. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered within 24 hours. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered within 12 hours. In some embodiments,Compound 1, or a pharmaceutically acceptable salt or solvate thereof,and the glucocorticoid are administered within 8 hours. In someembodiments, Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, and the glucocorticoid are administered within 6 hours.In some embodiments, Compound 1, or a pharmaceutically acceptable saltor solvate thereof, and the glucocorticoid are administered within 4hours. In some embodiments, Compound 1, or a pharmaceutically acceptablesalt or solvate thereof, and the glucocorticoid are administered within2 hours. In some embodiments, Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered within 1 hour. In some embodiments, Compound 1, or apharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered within 30 minutes. In some embodiments,Compound 1, or a pharmaceutically acceptable salt or solvate thereof,and the glucocorticoid are administered within 10 minutes.

In some embodiments, the glucocorticoid is beclomethasone,betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone,methylprednisolone, prednisolone, prednisone, or triamcinolone. In someembodiments, the glucocorticoid is hydrocortisone.

In some embodiments, the glucocorticoid is hydrocortisone and the doseadministered is less than the recommended dose of 15-25 mg/day.

In some embodiments, the glucocorticoid is prednisone and the doseadministered is less than the recommended dose of 5-7.5 mg/day.

In some embodiments, the glucocorticoid is prednisolone and the doseadministered is less than the recommended dose of 4-6 mg/day.

In some embodiments, the glucocorticoid is dexamethasone and the doseadministered is less than the recommended dose of 0.25-0.5 mg/day.

Disclosed herein is a method of treating congenital adrenal hyperplasia(CAH) in a subject in need thereof, comprising administering acombination of Compound 1, or a pharmaceutically acceptable salt orsolvate thereof; a glucocorticoid; and optionally a mineralcorticoid. Insome embodiments, the mineralocorticoid is fludrocortisone and the doseis less than the recommended dose of 0.05-0.2 mg/day.

EXAMPLES

The following examples further illustrate the invention but should notbe construed as in any way limiting its scope. In particular, theprocessing conditions are merely exemplary and can be readily varied byone of ordinary skill in the art.

All methods described herein can be performed in a suitable order unlessotherwise indicated herein or otherwise clearly contradicted by context.The use of any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. Unless defined otherwise, technical and scientificterms used herein have the same meaning as is commonly understood by oneof skill in the art to which this invention belongs.

Example 1: Pharmaceutical Composition

The pharmaceutical composition is manufactured as size 1 white hardgelatin capsules containing 200 mg of Compound 1 micronized to andaverage size of 10 microns or less. The pharmaceutical compositioncontains no additional excipients.

Example 2: Stability of the Pharmaceutical Composition Stability DataSummary

A summary of the pharmaceutical composition stability studies isprovided in Table 1. The pharmaceutical composition is a Compound 1neat-filled into size 0 capsules with no added excipients, in 3 strengthconfigurations: 1-mg, 5-mg, and 50-mg. The capsules were blisterpackaged in a polyvinyl chloride (PVC)-based film.

Under long term and accelerated conditions, no significant trend wasobserved in the three lots for any of the attributes evaluatedthroughout the course of the stability study.

TABLE 1 Summary of Stability Stability Available Lot Number Strength CCSConditions Data #1  1-mg PVC-based 25° C./60% RH 6 months blister pack40° C./75% RH 6 months #2  5-mg PVC-based 25° C./60% RH 6 months blisterpack 40° C./75% RH 6 months #3  50-mg PVC-based 25° C./60% RH 6 monthsblister pack 40° C./75% RH 6 months #4 200-mg 75 mL HDPE 25° C./60% RH 1month bottle 40° C./75% RH 9 months #5 200-mg 30 mL HDPE 25° C./60% RH 6months bottle 40° C./75% RH 6 months #6 200-mg 30 mL HDPE 25° C./60% RH6 months bottle 40° C./75% RH 6 months CCS = container closure system;CRC = child-resistant closure; DoM = date of manufacture; HDPE = highdensity polyethylene; PVC = polyvinyl chloride

Stability Protocols

The stability protocol for various pharmaceutical compositions isprovided in Table 2, 3, and 4.

TABLE 2 Stability Protocol Time (months) Test Acceptance Criteria T₀ 1 36 Appearance Size 0 blue capsule containing X A, B A, B A, B yellowpowder, blister pack and foil backing intact Assay Report (% LabelClaim) X A, B A, B A, B Related Report RRT and % each X A, B A, B A, BSubstances individual species and total Disintegration Report X A, B A,B A, B RRT = relative retention time X-testing performed at the timestudy was initiated A-samples stored under long term conditions of 25 ±2° C./60 ± 5% RH B-samples stored under accelerated conditions of 40 ±2° C./75 ± 5% RH

TABLE 3 Stability Protocol (200-mg capsules in 30 mL HDPE bottles) Time(months) Test Acceptance Criteria T₀ 1 3 6 Appearance Size 1 whitecapsule X A, B A, B A, B containing an off-white to yellow powder Assay(% LC) 90.0-110.0 X A, B A, B A, B Related Substances ≤1.0 X A, B A, BA, B Any Unspecified ≤2.0 Impurity (%) Total Impurities (%)Disintegration (min) NMT 15 X A, B A, B A, B Water Activity Reportresult X A, B A, B A, B LC = label claim; NMT = not more than X-testingperformed at the time study was initiated A-samples stored under longterm conditions of 25 ± 2° C./60 ± 5% RH B-samples stored underaccelerated conditions of 40 ± 2° C./75 ± 5% RH

TABLE 4 Stability Protocol (200-mg capsules in 30 mL HDPE bottles) forLots to be Used in Phase 2 Clinical Study Acceptance Time (months) TestCriteria T₀ 1 3 6 9 12 Appearance Size 1 white X B A, B A, B A A capsulecontaining an off-white to yellow powder Assay (% LC) 90.0-110.0 X B A,B A, B A A Related Substances ≤1.0 X B A, B A, B A A Any Unspecified≤2.0 Impurity (%) Total Impurities (%) Disintegration (min) NMT 15 X BA, B A, B A A Water Activity Report result X n/a n/a n/a A A MicrobialNMT 2000 CFU/g X n/a n/a n/a A A Enumeration NMT 200 CFU/g Total AerobicMicrobial Count (CFU/g) Total Combined Yeast and Mold (CFU/g) Count Testfor Specified Absent X n/a n/a n/a A A Microorganisms E. coli (/g) CFU =colony forming units; LC = label claim; n/a = not applicable; NMT = notmore than X-testing performed at the time study was initiated A-samplesstored under long term conditions of 25 ± 2° C./60 ± 5% RH B-samplesstored under accelerated conditions of 40 ± 2° C./75 ± 5% RH

The supportive data demonstrate that the pharmaceutical composition isstable for a minimum of 6 months (end of study). No adverse trends wereobserved under long term and accelerated conditions. The assay resultswere consistent through the entire study and no new related substancesspecies were observed during the stability study. The reported stabilityresults for lots stored in a blister packaging configuration areconsidered supportive for the updated packaging configuration of a 30-mLHDPE bottle, induction seal, and a child resistant cap. There are noexcipients in either configuration and both configurations provideprotection from light.

Example 3: Phase 1 Clinical Studies

Compound 1 has been investigated in 2 Phase 1 studies in healthy adultvolunteers.

Study 1 was the first-in-human study that investigated the safety,tolerability, and PK of single-escalating doses of Compound 1, givenorally, to healthy adult subjects. Safety and tolerability assessmentswere made over a wide range of single oral doses, and dose escalationdid not proceed until safety data from the preceding doses had beenreviewed. The data from this study were used for the selection of dosesfor Study 2.

The 2-part multiple-dose study, Study 2, determined the safety andtolerability of repeated daily doses of Compound 1 and investigated theeffects on biomarkers of relevance for the treatment of alcoholdependence. Part B investigated the interaction of Compound 1 withmidazolam (a cytochrome P450 3A4 [CYP3A4] substrate), determiningwhether Compound 1 significantly inhibited the metabolism of drugs thatare metabolized by CYP3A4.

In Study 1, Compound 1 was administered to healthy adult subjects as asingle PO dose of 2, 10, 50, 150, 400, or 800 mg in the fed state and150 mg in the fasted state. Absorption occurred moderately late,achieving peak C_(max) between 4 to 6 hours following dosing in the fedstate.

Table 5 provides a summary of the PK parameters at each dose level. WhenCompound 1 was given in the fed state, median time to reach maximumplasma concentration (T_(max)) occurred between 4 and 6 hours. Themedian T_(max) was 10.05 hours when Compound 1 was given in the fastedstate at 150 mg and ranged between 6 and 12 hours, suggesting possibledelayed absorption in the fasted state. Mean half-life (t_(1/2)) after asingle PO dose (fed and fasted state) was between 31 and 44 hours,ranging from 11 to 101 hours. Apparent volume of distribution (V_(z)/F)was large and appeared highly variable with greatest variabilityobserved at the 2 highest dose levels of 400 mg and 800 mg.

TABLE 5 Summary of Pharmacokinetic Parameters of Compound 1 FollowingSingle Oral Dose Administration in Healthy Volunteers (all Fed)Geometric Mean (CV %) Analyte = Plasma Compound PK 1 Parameters 2 mg 10mg 50 mg 150 mg 400 mg 800 mg N 6   6   6   6   6   6   C_(max) (ng/ 0.867  3.01 19.5  93.4  207    382    mL) (53)   (87)   (39)   (22)  (92)   (110)    T_(max)ª (h)  6.00  4.00  4.00  4.00  4.00  6.00(4.00-6.00) (2.00-6.00) (3.00-6.00) (3.00-6.00) (3.00-6.00) (4.00-6.00)t_(1/2)b (h) NC NC 31   29.2  44.2  41.9  (NC) (NC) (10.8-53.4)(20.0-41.5) (20.2-101)  (24.1-67.8) AUC_(0-t) _(last) NC NC 152   891    2300    4390    (ng · h/mL) (NC) (NC) (60)   (26)   (103)   (100)    AUC_(0-∞) NC NC 165    956    2580    4850    (ng · h/mL) (NC)(NC) (64)   (25)   (93)   (95)   CL/F (L/h) NC NC 302    157    155   165    (NC) (NC) (64)   (25)   (93)   (95)   V_(z)/F (L) NC NC 13500    6620    9890    9970    (NC) (NC) (45)   (38)   (212)    (144)   V_(ss)/F (L) NC NC 8080    4600    6580    6820    (NC) (NC) (36)  (33)   (152) (120) AUC = area under the plasma concentration-time curve;CL/F = oral clearance; C_(max) = maximum plasma concentration; CV =coefficient of variation; NC = not calculable; t_(1/2) = eliminationhalf-life; T_(max) = time to reach maximum plasma concentration;V_(ss)/F = volume of distribution at steady state; V_(z)/F = volume ofdistribution at terminal phase ^(a)Median (range) b Geometric mean(range)

As part of this single-dose escalation study, a food effect PKinvestigation was performed to examine Compound 1 exposures in both thefed and fasted states at the 150-mg dose level. A total of 6 subjectswere administered 150 mg Compound 1 in each of these 2 dosing groups. Ofthese 6 subjects, 4 subjects received Compound 1 at the same dose inboth fed and fasted states. The administration of Compound 1 in thefasted state resulted in a much flatter mean concentration-time (i.e.,with significantly lower absorption) profile when compared against themean profile at the same dose, given within 5 minutes after astandardized breakfast meal. The mean AUC_(0-∞), and C_(max) values fora 150-mg dose in the fed state was approximately 3- and 11-fold greaterthan that of the fasted state, respectively. Table 6 provides a summaryof the PK parameters at the 150-mg dose level under both fed and fastedstate conditions.

TABLE 6 Summary of Pharmacokinetic Parameters of Compound 1 FollowingSingle Oral Dose Administration in Healthy Volunteers-Fed vs. FastedState Geometric Mean (CV %) Pharmacokinetic Analyte = Plasma Compound 1Parameters 150 mg Fed 150 mg Fasted N  6   6  C_(max) (ng/ml)  93.4  8.22 (22)  (83)  T_(max)ª (h)   4.00  10.05 (3.00-6.00)  (6.00-12.00)t_(1/2) ^(b) (h)  29.2  38.4 (20.0-41.5) (24.2-88.5) AUC_(0-t) _(last)(ng · h/mL) 891   288   (26)  (48)  AUC_(0-∞) (ng · h/mL) 956   331  (25)  (44)  CL/F (L/h) 157   454   (25)  (44)  Vz/F (L) 6620   25100(81) (38)  Vss/F (L) 4600   25200    (33)  (68)  AUC = area under theplasma concentration-time curve; CL/F = apparent total body clearance;C_(max) = maximum plasma concentration; CV = coefficient of variation; N= number of subjects; NC = not calculable; PK = pharmacokinetic; T_(max)= time to reach maximum plasma concentration; t½ = eliminationhalf-life; V_(ss)F = apparent volume of distribution at steady stateduring the terminal phase after extravascular administration; V_(z)/F =apparent volume of distribution during the terminal phase afterextravascular administration. ^(a)Median (range) ^(b)Geometric mean(range)

PK parameters AUC_(0-∞) and C_(max) were analyzed separately for doseproportionality for Compound 1 from 50 to 800 mg when administered inthe fed state. The analysis results suggested that for every doubling ofdose, AUC_(0-∞) can be expected to increase 1.74 times more than whatwould be expected under dose proportionality. C_(max) appeared more thandose proportional but the formal test was inconclusive as the 90%confidence interval were partially within the 0.8-1.25 interval. Doseproportionality across administered doses in the fed state could not beconcluded on the basis of AUC_(0-∞) or C_(max).

PK were also evaluated in the multiple-dose, dose-escalation study,Study 2. In Part A of the study, subjects were divided into 3 cohortsand received 50, 150, or 200 mg Compound 1 or placebo for 14 consecutivedays (at least 6 subjects received Compound 1 and 2 subjects receivedplacebo in each cohort). Blood concentrations of Compound 1 were closeto steady-state levels after 2 weeks of dosing and the accumulationratio was between 2.51 to 3.65. Part B investigated the interaction ofCompound 1 with midazolam (a CYP3A4 substrate), thereby determiningwhether this compound significantly inhibited the metabolism of drugsthat are metabolized by CYP3A4 serial blood samples were collected todetermine plasma concentrations of study drug after a single dose ofCompound 1 had been administered and at steady state. All dosingoccurred in the fed state. An assessment of diurnal cortisol levels,plus when under conditions of glucose clamp, were also carried out bothprior to and during the dosing period.

Overall concentration time profiles of Compound 1 showed that absorptionwas moderately delayed with C_(max) achieved at a median of 5 hoursfollowing oral dosing. Consistent with the single-dose study (Study 1),concentrations appeared to decline in a bi-exponential manner,characterized by a rapid decrease within the first 24 hours. Followingmultiple daily dosing for 2 weeks, the t_(1/2) of Compound 1 exceeded100 hours; therefore, an accumulation ratio of Compound 1 was between2.51 to 3.65 (see Table 7). The T_(max) appeared to be consistent acrossdoses. Overall half-lives, weight normalized CL/F and V/F wereconsistent for 150 and 200 mg. However, the values for these latter 2parameters were almost doubled at the 50-mg dose level. Variability (CV%) for apparent clearance and volume of distribution were large and notreduced with weight-normalization.

TABLE 7 Summary of Noncompartmental Pharmacokinetic Parameters ofCompound 1 After Single (Day 1) and Multiple (Day 14) Oral Doses of 50mg, 150 mg, and 200 mg of Compound 1 in Part A of the Study GeometricMean (CV %) 50 mg 150 mg 200 mg 50 mg 150 mg 200 mg Day 1 Day 1 Day 1Day 14 Day 14 Day 14 N 8   9   7    8    9    6  C_(max) (ng/mL) 22.7 127   143    50.3  222   314  (59)   (52)    (62)    (56)    (58)   (93)  T_(max) ª (hr)  4.52  5.00   5.00    5.00    5.00    5.00 (3.00-(5.00- (2.00- (3.00- (3.00- (3.00- 10.00) 6.00) 5.00) 5.00) 5.03) 5.00)Effective t_(1/2) ^(b) NC NC NC   37.7   32.7   52.0 (hr) NC NC NC  (27.4)   (29.7) AUC_(0-∞) NC NC NC  980   4680   5660  (ng · hr/mL) NCNC NC   (53.8)  (104)   (122)  AUC_(0-24 h) 97.6  590   559   273  1480   2040  (ng · hr/mL) (58)   (56)   (55^(c))   (56)    (66)   (98)  C_(avg) (ng/mL) NC NC NC   11.4   61.7   85.0 NC NC NC   (56)   (66)    (98)  CL_(aa)/F (L/hr) NC NC NC  183   101    98  NC NC NC  (56)    (66)    (98)  WT-norm Cl_(aa)/F NC NC NC    2.88    1.42   1.50 (L/hr/kg) NC NC NC   (46.9)   (72.9)   (89.9) Vz/F (L) NC NC NC33500  17600  16300  NC NC NC   (90)    (59)    (76)  Vss/F (L) NC NC NC12900   6170   5080  NC NC NC   (91)    (40)    (78)  WT-norm Vss/F(L/kg) NC NC NC  204    86.5   77.4 NC NC NC   (71.3)   (41.0)   (68.6)NC NC NC    2.80    2.51    3.65 R_(A) NC NC NC   (27.4)   (29.7)  (34.4) AUC = area under the plasma concentration-time curve; CL/F =apparent clearance; C_(max) = maximum plasma concentration; RA =accumulation ratio calculated as Day 14 AUC₀₋₂₄/Day 1 AUC₀₋₂₄; t½ =terminal half-life; effective t½ = half-life calculated by accumulationratio; Tmax = time to maximum plasma concentration; Vss/F = volume ofdistribution at steady state; Vz/F = volume of distribution at terminalphase; WT-norm = weight normalized ^(a) Median (range). ^(b) Geometricmean (range). ^(c) n = 6, Dropout Subject 306 not included in thecalculation of summary statistics.

Table 8 presents the results of the dose proportionality assessment forthe AUC₀₋₂₄ and C_(max) over the tested dose range. For AUC₀₋₂₄ andC_(max), the adjusted mean slope at Day 1 and Day 14 were all above thevalue of 1, suggesting a slightly more than proportional increase ofAUC₀₋₂₄ and C_(max) values with increasing doses.

TABLE 8 Summary of Assessment of Dose Proportionality as Assessed by thePower Model for Plasma Compound 1 Standard 90% CI for Parameter Day MeanSlope Error Slope CV % AUC₀₋₂₄ 1 1.40 0.194 (1.069, 59.3 (ng hr/mL)1.737) 14 1.48 0.221 (1.104, 69.1 1.864) C_(max) (ng/ml) 1 1.41 0.185(1.092, 57.5 1.728) 14 1.33 0.210 (0.972, 64.8 1.693) AUC = area underthe plasma concentration-time curve; C_(max) = maximum plasmaconcentration

Safety

The safety of Compound 1 was evaluated in 2 Phase 1 studies in healthyadult volunteers (Study 1 and Study 2). In both studies, adverse events(AEs), clinical laboratory tests, vital signs (supine blood pressure andpulse rate), and electrocardiograms (ECGs) were evaluated. Overall, inStudy 1, Compound 1 was well-tolerated.

Compound 1, when administered as multiple doses up to 200 mg, wasgenerally well tolerated in the healthy subject population studied. InStudy 1, the effects upon biomarkers of relevance for the treatment ofalcohol dependence were investigated. Five clusters of an AddictionResearch Center Inventory Questionnaire (ARCI-49) were used to comparethe effect of Compound 1 vs. placebo: Morphine-Benzedrine Group Scalemeasuring euphoria; Lysergic-Acid-Diethylamide Group Scale estimatingdysphoric and somatic changes; Pentobarbital-Chlorpromazine-AlcoholGroup Scale measuring sedation; Benzedrine Group (BG) Scale measuringintellectual efficiency and energy; Amphetamine Group Scale measuringeffects of d-amphetamine, respectively. No systematic pattern ordose-response for the change from baseline or for the difference overplacebo in each cluster was observed.

In summary, single, oral doses up to 800 mg and multiple doses up to 200mg of Compound 1 were well-tolerated by healthy male and femalesubjects.

Example 4: Phase 2 Clinical Studies

Cohort A of the Phase 2 Study includes a 6-week, multiple-dose, doseescalation study of Compound 1 for the treatment of adults with classicCAH. After screening, eligible patients will be enrolled into a 6-weektreatment period followed by a 4-week washout/safety follow-up period.

This cohort will be conducted in approximately 9 patients, who willreceive Compound 1 daily for up to 6 weeks. Compound 1 will beadministered as an oral daily dose. Patients will undergo titration ofCompound 1 through three escalating dosage strengths at 2-weekintervals. Patients will have overnight PK/PD assessments performed atbaseline, which include an pre-dose overnight assessment and a post-doseovernight assessment for PK/PD following administration of the firstdose. At the end of each 2-week dosing period, patients will return forsingle overnight visits for steady-state PK/PD assessments. A follow-upoutpatient visit will occur 30 days after their last dose. Uponcompletion of the initial cohort (Cohort A), the study will proceed to amultiple ascending dose (MAD) design with up to 3 sequential cohorts(Cohorts B, C, and D) to further evaluate the safety, PK, and PD ofvarious SPR001 dosing regimens and to identify an optimal dose regimen.Each cohort will undergo a 2-week run-in period, a 2-week treatmentperiod, and a 30-day washout and safety follow-up period. During therun-in period, which will occur during screening, subjects will documentin a paper diary each dose of glucocorticoid medication taken, the timeof each meal, and the time they went to bed and woke up each day, toensure compliance with background glucocorticoid regimens and thestability of their daily routine.

Patients in Cohort B will receive study drug at 200 mg BID, with a dosein the morning and a dose in the evening, either with a meal orconsumption of a standardized snack. For Cohorts C and D, the dose leveland the frequency and timing of dosing will be determined based oninterim data from the previous cohorts. However, the dose level of eachsuccessive cohort will be capped at twice the daily dose level of theprevious cohort.

Study Design

-   -   Study Type: Interventional    -   Primary Purpose: Treatment    -   Study Phase: Phase 2    -   Interventional Study Model: Sequential Assignment    -   Number of Cohorts: Up to 4    -   Masking: No masking    -   Allocation: Non-Randomized    -   Enrollment: Up to approximately 27 [Anticipated]

Arms and Interventions

Assigned Arms Interventions Experimental: Cohort A Drug: Compound 1 Thefirst cohort of 9 patients will be administered 200-mg capsules Compound1 at dose strength of 200 mg daily for 2 weeks, and escalating through600 mg per day for 2 weeks and 1,000 mg per day for 2 weeks.Experimental: Cohort B Drug: Compound 1 Cohort B patients will beadministered Compound 200-mg capsules 1 at a dose strength of 200 mgtwice daily (BID) for 2 weeks. Experimental: Cohort C Drug: Compound 1The dose/dose regimen for Cohort C will be 50-mg or 200 mg determinedbased on an interim review of safety capsules and PK/PD data from theprevious Cohorts Experimental: Cohort D Drug: Compound 1 The dose/doseregimen for Cohort C will be 50-mg or 200 mg determined based on aninterim review of safety capsules and PK/PD data from the previousCohorts

Outcome Measures Primary Outcome Measure:

-   -   1. To evaluate the safety of Compound 1 in subjects with CAH.    -   2. To assess the efficacy of Compound 1 in subjects with classic        CAH as measured by percent and absolute change in 17-OHP        compared to baseline.

Secondary Outcome Measure:

-   -   3. To explore the dose(s) of Compound 1 that cause        pharmacodynamics changes in plasma concentrations of ACTH,        androstenedione, and testosterone, as measured by the absolute        and percent change from baseline by dose.    -   4. To determine pharmacokinetics of Compound 1 in subjects with        CAH.    -   5. To explore potential relationships between pharmacodynamics        and pharmacokinetics.

Exploratory

-   -   6. To explore the dose(s) of Compound 1 that cause changes in        pharmacodynamics biomarkers in urine, as measured by the        absolute and percent change from baseline by dose.

Eligibility

-   -   Minimum Age: 18 Years    -   Maximum Age:    -   Sex: All    -   Gender Based: No    -   Accepts Healthy Volunteers: No    -   Criteria: Inclusion

Criteria: Inclusion Criteria:

-   -   Male and female patients age 18 or older.    -   Documented diagnosis of classic CAH due to 21-hydroxylase        deficiency    -   Elevated 17-OHP at screening    -   On a stable glucocorticoid replacement regimen for a minimum of        30 days

Exclusion Criteria:

-   -   Clinically significant unstable medical condition, illness, or        chronic disease    -   Clinically significant psychiatric disorder.    -   Clinically significant abnormal laboratory finding or assessment    -   History of bilateral adrenalectomy or hypopituitarism    -   Pregnant or nursing females    -   Use of any other investigational drug within 30 days    -   Unable to understand and comply with the study procedures,        understand the risks, and/or unwilling to provide written        informed consent.

Results:

The phase 2 study showed that Compound 1 was generally well-tolerated.The study established a range of safe doses after exploring a wide rangeof doses (5-fold range) (see FIG. 1 ).

With respect to patient-level response to Compound 1, 80% showed reducedACTH (see FIG. 2 ). Generally, attenuation of ACTH demonstrates targetengagement and functional CRF₁ receptor antagonism. 80% of patientsubjects demonstrated reduction in ACTH. 70% of subject demonstratedmore than 25% reduction in ACTH. 40% of subjects were in the normalrange after treatment.

A reduction of 17-OHP demonstrates “control” of the disease based onStandard guidelines. This allows for steroid taper. 80% of subjectsdemonstrated reduction in 17-OHP (see FIG. 3 ). 50% of subjectsdemonstrated more than 25% reduction in 17-OHP. 50% of subjects werewithin the guideline range (1200 ng/dL) after treatment.

Compound 1 attenuates morning rise in A4 which indicates an ability tocontrol excess androgen production and associated symptoms (see FIG. 4). 100% of subjects demonstrated reduction in Androstenedione (atvarious doses). 60% of subjects demonstrated more than 25% reduction inAndrostenedione. 50% of subjects were within normal reference rangeafter treatment.

Example 5: 3-Month Phase 2 Study

This is a 3-month Phase 2 study to evaluate the safety and efficacy ofCompound 1 in subjects with classic CAH. This study will investigate theextended use of Compound 1 over a 3-month period in combination withreplacement glucocorticoids and mineralocorticoids in the treatment ofCAH.

This study will enroll up to approximately 24 eligible subjects who willreceive Compound 1 daily for up to 3-months. Compound 1 will beadministered as an oral daily dose. At the end of each 2-week dosingperiod, patients will return for morning laboratory assessments. Afollow-up outpatient visit will occur 30 days after their last dose.

Study Design

-   -   Study Type: Interventional    -   Primary Purpose: Treatment    -   Study Phase: Phase 2    -   Interventional Study Model: Sequential Assignment    -   Number of Arms: 1    -   Masking: No Masking    -   Allocation: Non-Randomized    -   Enrollment: Up to approximately 24 [anticipated]

Outcome Measures Primary Outcome Measure:

-   -   1. To evaluate the safety of Compound 1 in subjects with CAH.

Second Outcome Measure:

-   -   2. To evaluate the efficacy of Compound 1 in subjects with CAH        in terms of changes in hormones.

Exploratory:

-   -   3. To evaluate the effect of Compound 1 on quality of life,        metabolic parameters, exploratory adrenal hormones, and semen        analysis in subjects with CAH.

Eligibility:

-   -   Minimum Age: 18 Years    -   Maximum Age:    -   Sex: All    -   Gender Based: No    -   Accepts Healthy Volunteers: No    -   Criteria: Inclusion

Criteria: Inclusion Criteria:

-   -   Male and female patients age 18 or older.    -   Documented diagnosis of classic CAH due to 21-hydroxylase        deficiency    -   Elevated 17-OHP at screening    -   On a stable glucocorticoid replacement regimen for a minimum of        30 days

Exclusion Criteria:

-   -   Clinically significant unstable medical condition, illness, or        chronic disease    -   Clinically significant psychiatric disorder.    -   Clinically significant abnormal laboratory finding or assessment    -   History of bilateral adrenalectomy or hypopituitarism    -   Pregnant or nursing females    -   Use of any other investigational drug within 30 days    -   Unable to understand and comply with the study procedures,        understand the risks, and/or unwilling to provide written        informed consent.

Example 6: Adolescent Study

This is a Phase 2, open-label, multiple-dose study designed to provideproof of concept for the use of Compound 1 to treat adolescents 12 to 17years of age with classic CAH. The study will evaluate the safety,efficacy, and PK of 2 weeks of treatment with Compound 1. Each subjectwill undergo a 2-week diary run-in period during screening, a 2-weektreatment period, and a 30-day washout and safety follow-up period.

An adaptive design with up to 3 sequential dose cohorts (Cohorts 1, 2,and 3) is planned to identify an optimal dose strength and regimen inadolescents with classic CAH. Each cohort will initially enroll 3subjects and may later enroll 3 more subjects based on interim data fromthe first 3 subjects, for a total of 6 subjects per cohort. However, ifsafety, efficacy, and PK results from 6 subjects are inconclusive, acohort may be expanded up to a maximum of 12 subjects. Cohort 1 willreceive study drug at 200 mg QD. Cohorts 2 and 3 will be sequentiallyactivated only if further investigation of an optimal dose strength orregimen is required; the dose strength and frequency and timing ofdosing for these cohorts will be determined based on interim data fromthe previous cohort(s). However, the dose strength administered to eachsuccessive cohort will be capped at twice the daily dose strengthadministered to the previous cohort.

This study will enroll patients with inadequately controlled CAH despitean existing glucocorticoid (GC) regimen (including anycurrently-available regimen: hydrocortisone, prednisone/prednisolone,and/or dexamethasone). In practice, CAH patients are typically treatedwith supraphysiologic doses of GCs which are both toxic and noteffective in many adolescent patients. In this population, GCs areassociated with multiple well-described short- and long-term toxicitiesincluding: growth retardation, weight gain, hypertension, hyperglycemia,hyperlipidemia, and Cushingoid features.

The objective of treatment of this patient population with Compound 1 isreduction (or normalization) of key hormonal outcome measures whichcould allow reduction of their GC replacement requirements which willimprove clinical outcomes of concern, including growth velocity.Improvement of hormonal outcome measures in this population are alsoexpected to delay premature puberty and bone maturation, ultimatelyleading to improvements in height in adolescents with CAH.

Outcome Measures Primary Outcome Measures:

-   -   1. To evaluate the safety of Compound 1 in adolescent subjects        with CAH.

Secondary Outcome Measures:

-   -   2. To evaluate the dose(s) of Compound 1 that cause changes in        key pharmacodynamics biomarkers in blood in adolescent subjects        with CAH.    -   3. To investigate the effect of Compound 1 on quality of life in        adolescent subjects with CAH.    -   4. To determine the pharmacokinetics of Compound 1 in adolescent        subjects with CAH.    -   5. To investigate potential relationships between        pharmacodynamics and pharmacokinetics in adolescent subjects        with CAH.

Exploratory

-   -   6. To explore the dose(s) of Compound 1 that cause changes in        exploratory pharmacodynamics biomarkers in blood and urine in        adolescent subjects with CAH.

Eligibility Criteria Inclusion Criteria:

-   -   Male and female subjects 12 to 17 years of age, inclusive    -   Documented diagnosis of classic CAH due to 21-hydroxylase        deficiency    -   Elevated 17-OHP at screening    -   On a stable regimen of glucocorticoid replacement for minimum of        30 days

Exclusion Criteria:

-   -   Clinically significant unstable medical condition, illness, or        chronic disease    -   Clinically significant psychiatric disorder.    -   Clinically significant abnormal laboratory finding or assessment    -   History of bilateral adrenalectomy or hypopituitarism    -   Pregnant or nursing females    -   Use of any other investigational drug within 30 days    -   Unable to understand and comply with the study procedures,        understand the risks, and/or unwilling to provide written        informed consent.

Example 7: Phase 3 Clinical Studies

This is a 24-week, randomized, double-blind, placebo-controlled study ofCompound 1 for the treatment of classic CAH. After screening, eligiblepatients will be enrolled into a 24-week treatment period followed by a4-week safety follow-up period.

Subjects in the study will be randomized in a 1:1 ratio to eitherreceive Compound 1 or a matching placebo for up to 24 weeks. Compound 1or a placebo will be administered as an oral daily dose. Patients willreturn approximately monthly for study visits. A follow-up outpatientvisit will occur 30 days after their last dose. It is initially plannedthat up to approximately 150 patients will be enrolled.

Consistent with the design of the Phase 2 study, the Phase 3 clinicalstudy will seek to enroll patients with inadequately controlled CAHdespite an existing glucocorticoid (GC) regimen (including anycurrently-available regimen: hydrocortisone, prednisone/prednisolone,and/or dexamethasone). In practice, CAH patients are typically treatedwith supraphysiologic doses of GCs which are both toxic and noteffective in the majority of patients. GCs are associated with multiplewell-described short- and long-term toxicities in adults including:excessive weight gain, hypertension, hyperglycemia, hyperlipidemia, andCushingoid features.

Study Design:

-   -   Study Type: Interventional    -   Primary Purpose: Treatment    -   Study Phase: Phase 3    -   Interventional Study Model: Randomized Controlled Trial    -   Allocation: Randomized    -   Enrollment: 150 [Anticipated]

Outcome Measures Primary Outcome Measures

-   -   1. Evaluate efficacy of Compound 1 in reducing A4 and 17-OHP in        patients with CAH.

Secondary Outcome Measures

-   -   2. Evaluate efficacy of Compound 1 in patients with CAH in terms        of changes in key hormones.    -   3. Evaluate efficacy of Compound 1 in improving quality of life        and/or mood in patients with CAH.    -   4. Evaluate efficacy of Compound 1 in improving hyperandrogenic        symptoms in patients with CAH.    -   5. Evaluate efficacy of Compound 1 in improving metabolic        parameters in patients with CAH.    -   6. Evaluate safety of Compound 1 in patients with CAH.

Eligibility

-   -   Minimum age: 16 Years    -   Maximum Age:    -   Sex: All    -   Gender Based: No    -   Accepts Healthy Volunteers: No    -   Criteria: Inclusion

Criteria

Inclusion Criteria:

-   -   Male and female patients age 16 or older.    -   Document diagnosis of classic CAH due to 21-hydroxylase        deficiency    -   Elevated 17-OHP    -   On a stable glucocorticoid replacement regimen for a minimum of        30 days

Exclusion Criteria:

-   -   Clinically significant unstable medical condition, illness, or        chronic disease    -   Clinically significant psychiatric disorder.    -   Clinically significant abnormal laboratory finding or assessment    -   History of bilateral adrenalectomy or hypopituitarism    -   Pregnant or nursing females    -   Use of any other investigational drug within 30 days    -   Unable to understand and comply with the study procedures,        understand the risks, and/or unwilling to provide written        informed consent.

Example 8: Phase 3 OLE and Steroid Sparing Studies

Upon completion of the study described in Example 7, eligible patientswill then be offered the opportunity to enroll into an open labelextension study lasting up to 1 year. The open label study will allowall eligible patients to receive active study drug during theirparticipation in the Phase 3 program. Patients will undergo studyassessments every 1-3 months during the open label phase, and will beevaluated for long-term safety and efficacy (including both hormonalendpoints and long-term clinical outcome measures of concern in thispopulation).

A further study may seek to enroll patients with inadequately controlledCAH despite an existing glucocorticoid (GC) regimen (including anycurrently-available regimen: hydrocortisone, prednisone/prednisolone,and/or dexamethasone). Such CAH patients are typically treated withsupraphysiologic doses of GCs which are both toxic and not effective inthe majority of patients. GCs are associated with multiplewell-described short- and long-term toxicities in adults including:excessive weight gain, hypertension, hyperglycemia, hyperlipidemia, andCushingoid features.

Following a period of treatment (for example 12 weeks) during the doseof GC will be kept stable, patients in this study will have their doseof GC progressively reduced from a supraphysiologic dose to a lower doseat or close to a dose equivalent to a physiologic dose of GC.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

1.-180. (canceled)
 181. A method of treating congenital adrenalhyperplasia (CAH), hyperandrogenic symptoms, menstrual irregularity,ovulatory dysfunction or infertility in a subject, comprising:administering Compound 1:

or a pharmaceutically acceptable salt or solvate thereof, at a dosebetween about 50 mg/day and about 800 mg/day.
 182. The method of claim181, wherein Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose between about 50 mg/day andabout 200 mg/day.
 183. The method of claim 181, wherein Compound 1, or apharmaceutically acceptable salt or solvate thereof, is administered ata dose of about 200 mg/day.
 184. The method of claim 181, whereinCompound 1, or a pharmaceutically acceptable salt or solvate thereof, isadministered at a dose of about 100 mg/day.
 185. The method of claim181, wherein Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, is administered at a dose of about 75 mg/day.
 186. Themethod of claim 181, wherein Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, is administered at a dose of about50 mg/day.
 187. The method of claim 181, the pharmaceutical compositionis administered once a day.
 188. The method of claim 181, furthercomprising administering a glucocorticoid.
 189. The method of claim 188,wherein the amount of glucocorticoid is reduced compared to a previouslyadministered dose of the glucocorticoid.
 190. The method of claim 189,wherein the reduced amount of glucocorticoid is a reduced daily dose ofthe glucocorticoid and the previously administered dose of theglucocorticoid is a previously administered daily dose of theglucocorticoid.
 191. The method of claim 189, wherein the amount ofglucocorticoid is reduced from a supraphysiologic amount to aphysiologic amount.
 192. The method of claim 189, wherein the amount ofglucocorticoid is reduced by about 5%, about 10%, about 15%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about55%, or about 60%.
 193. The method of claim 192, wherein symptomsassociated with high-dose glucocorticoid therapy are reduced, whereinthe symptoms associated with high-dose glucocorticoid therapy areobesity, insulin resistance, metabolic abnormalities, hypertension,cardiovascular diseases, or osteoporosis.
 194. The method of claim 188,wherein the glucocorticoid is beclomethasone, betamethasone, budesonide,cortisone, dexamethasone, hydrocortisone, methylprednisolone,prednisolone, prednisone, or triamcinolone.
 195. The method of claim194, wherein the glucocorticoid is hydrocortisone.
 196. The method ofclaim 195, wherein the hydrocortisone is administered at a dose lessthan about 10 mg/day.
 197. The method of claim 195, wherein thehydrocortisone is administered at a dose less than about 5 mg/day. 198.The method of claim 188, wherein Compound 1, or a pharmaceuticallyacceptable salt or solvate thereof, and the glucocorticoid areadministered concurrently.
 199. The method of claim 188, whereinCompound 1, or a pharmaceutically acceptable salt or solvate thereof,and the glucocorticoid are administered sequentially.
 200. The method ofclaim 199, wherein Compound 1, or a pharmaceutically acceptable salt orsolvate thereof, and the glucocorticoid are administered sequentiallywithin 24 hours.
 201. The method of claim 199, wherein Compound 1, or apharmaceutically acceptable salt or solvate thereof, and theglucocorticoid are administered sequentially within 2 hours.